Combination Products Challenge Regulators and Manufacturers

Combination products are high on everyone’s radar screen, as seen in continuing discussion about appropriate testing and regulation of self-injectors, such as EpiPen, and emerging cellular and gene therapies. Manufacturers complain of delays in decisions by FDA’s Office of Combination Products (OCP) about which FDA center should take the lead in evaluating a new combo. Medical device makers are particularly unhappy that most stents and transdermal patches are classified as drugs based on primary mode of action. At the same time, biopharma companies struggle with designing human-factors studies and evaluating risks related to intended use. A hot issue is how much the device portion of a generic drug–device combo has to be the “same” as the innovator product.

Industry concerns have generated efforts by FDA commissioner Robert Califf to streamline the OCP system for designating the lead center to regulate a new combination product. A newly formed Combination Products Council, composed of senior-level officials from OCP, the Center for Biologics Evaluation and Research (CBER), the Center for Drug Evaluation and Research (CDER), and the Center for Devices & Radiological Health (CDRH), was established in April 2016 to address cross-cutting issues and resolve disagreements. OCP also has established an early advisory process to discuss with manufacturers regulatory classification issues for a new combination product. OCP is working to finalize draft guidances on GMPs and on human factors studies for combination products, while several other guidances are in the works.

More support

Greater drug industry interest in these issues is apparent in an agreement to support combination product development with drug user fees. A new provision in the Prescription Drug User Fee Act (PDUFA VI) slated for Congressional approval in the coming months will provide funds to expand and train staff and promote more coordination between OCP and review centers. The program also will support drafting and publication of guidances on bridging studies and labeling, set goals for timely review of human factors study protocols, and fund an independent third-party evaluation of the combination products program.

Laurie Norwood, deputy director of CBER’s Division of Manufacturing and Product Quality, noted at the PDA/FDA Joint Regulatory Conference in Washington, D.C. in September 2016 that combination products were unrecognized 25 years ago, but now appear daily. OCP Senior Manager Melissa Burns described policies and processes for dealing with combos, emphasizing that drug companies don’t have to “reinvent the wheel” in documenting design controls for marketed products. She acknowledged that OCP needs to clarify for manufacturers how much data will be required to support manufacturing changes, an issue slated for future guidance. OCP deputy director Patricia Love admitted that many “live issues” have been raised by a draft guidance on conducting human factors studies, a project high on OCP’s agenda.

These and other questions related to developing and testing combination products in the United States and in other regions will be addressed further at a conference sponsored by the Drug Information Association (DIA) in late October 2016. Three Parenteral Drug Association courses in November 2016 will examine human factors in designing medical products. Legislation before Congress contains provisions designed to streamline oversight of these complex therapies that will generate further discussion in the coming year.